Development of a machine learning model to predict early recurrence for hepatocellular carcinoma after curative resection

Background: Early recurrence is common for hepatocellular carcinoma (HCC) after surgical resection, being the leading cause of death. Traditionally, the COX proportional hazard (CPH) models based on linearity assumption have been used to predict early recurrence, but predictive performance is limited. Machine learning models offer a novel methodology and have several advantages over CPH models. Hence, the purpose of this study was to compare random survival forests (RSF) model with CPH models in prediction of early recurrence for HCC patients after curative resection. Methods: A total of 4,758 patients undergoing curative resection from two medical centers were included. Fifteen features including age, gender, etiology, platelet count, albumin, total bilirubin, AFP, tumor size, tumor number, microvascular invasion, macrovascular invasion, Edmondson-Steiner grade, tumor capsular, satellite nodules and liver cirrhosis were used to construct the RSF model in training cohort. Discrimination, calibration, clinical usefulness and overall performance were assessed and compared with other models. Results: Five hundred survival trees were used to generate the RFS model. The five highest Variable Importance (VIMP) were tumor size, macrovascular invasion, microvascular invasion, tumor number and AFP. In training, internal and external validation cohort, the C-index of RSF model were 0.725 [standard errors (SE)=0.005], 0.762 (SE=0.011) and 0.747 (SE=0.016), respectively; the Gonen & Heller's K of RSF model were 0.684 (SE=0.005), 0.711 (SE=0.008) and 0.697 (SE=0.014), respectively; the time-Ddependent AUC (2 years) of RSF model were 0.818 (SE=0.008), 0.823 (SE=0.014) and 0.785 (SE=0.025), respectively. The RSF model outperformed ERASL model, Korean model, AJCC TNM stage, BCLC stage and Chinese stage. The RSF model is capable of stratifying patients into three different risk groups (low-risk, intermediate-risk, high-risk groups) in the training and two validation cohorts (all P<0.0001). A web-based prediction tool was built to facilitate clinical application (https://recurrenceprediction.shinyapps.io/surgery_ predict/). Conclusions: The RSF model is a reliable tool to predict early recurrence for patients with HCC after curative resection because it exhibited superior performance compared with other models. This novel model will be helpful to guide postoperative follow-up and adjuvant therapy.